Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study.

PURPOSE: To describe the health-related quality of life (HRQoL) of an unselected population of patients with chronic lymphocytic leukaemia (CLL) including untreated patients. METHODS: HRQoL was measured by the EORTC QLQ-C30 including the CLL16 module, EQ-5D, and VAS in an observational study over multiple years. All HRQoL measurements per patient were connected and analysed using area under the curve analysis over the entire study duration. The total patient group was compared with the general population, and three groups of CLL patients were described separately, i.e. patients without any active treatment ("watch and wait"), chlorambucil treatment only, and patients with other treatment(s). RESULTS: HRQoL in the total group of CLL patients was compromised when compared with age- and gender-matched norm scores of the general population. CLL patients scored statistically worse on the VAS and utility score of the EQ-5D, all functioning scales of the EORTC QLQ-C30, and the symptoms of fatigue, dyspnoea, sleeping disturbance, appetite loss, and financial difficulties. In untreated patients, the HRQoL was slightly reduced. In all treatment stages, HRQoL was compromised considerably. Patients treated with chlorambucil only scored worse on the EORTC QLQ-C30 than patients who were treated with other treatments with regard to emotional functioning, cognitive functioning, bruises, uncomfortable stomach, and apathy. CONCLUSIONS: CLL patients differ most from the general population on role functioning, fatigue, concerns about future health, and having not enough energy. Once treatment is indicated, HRQoL becomes considerably compromised. This applies to all treatments, including chlorambucil, which is considered to be a mild treatment.

Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40-60 years.

The preferred type of post-remission therapy (PRT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate, especially in patients at higher risk of nonrelapse mortality (NRM), including patients >40 years of age. We report results of a time-dependent multivariable analysis of allogenic hematopoietic stem cell transplantation (alloHSCT) (n=337) versus chemotherapy (n=271) or autologous HSCT (autoHSCT) (n=152) in 760 patients aged 40-60 years with AML in CR1. Patients receiving alloHSCT showed improved overall survival (OS) as compared with chemotherapy (respectively, 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following alloHSCT and autoHSCT in patients with intermediate-risk AML (60±4 vs 54±5%). However, alloHSCT was associated with less relapse (hazard ratio (HR) 0.51, P<0.001) and better relapse-free survival (RFS) (HR 0.74, P=0.029) as compared with autoHSCT in intermediate-risk AMLs. AlloHSCT was applied following myeloablative conditioning (n=157) or reduced intensity conditioning (n=180), resulting in less NRM, but comparable outcome with respect to OS, RFS and relapse. Collectively, these results show that alloHSCT is to be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged 40-60 years, whereas autoHSCT remains a treatment option to be considered in patients with intermediate-risk AML.

Real-world costs of chronic lymphocytic leukaemia in the Netherlands.

We performed a comprehensive cost calculation identifying the main cost drivers of treatment of chronic lymphocytic leukaemia in daily practice. In our observational study 160 patient charts were reviewed repeatedly to assess the treatment strategies from diagnosis till the study end. Ninety-seven patients (61%) received ≥1 treatment lines during an average follow-up time of 6.4 years. The average total costs per patient were €41,417 (€539 per month). The costs varied considerably between treatment groups and between treatment lines. Although patients were treated with expensive chemo(immuno-)therapy, the main cost driver was inpatient days for other reasons than administration of chemo(immuno-)therapy.

Guideline for diagnosis and treatment of Waldenström's macroglobulinaemia.

On behalf of the lymphoma and multiple myeloma working parties of the Dutch/Belgian Haemato-Oncology Foundation for Adults in The Netherlands (HOVON), we present a guideline for diagnosis and management of Waldenström's macroglobulinemia (WM). Considering the indolent behaviour and heterogeneous clinical presentation of WM, it is crucial to determine the right indications for treatment, as well as to individualise therapeutic options. There are significant differences from the approach to multiple myeloma or the treatment of other indolent non-Hodkgin lymphomas, and these results cannot always be extrapolated. There is a lack of large clinical trials due to the low incidence of WM. Based on the available data, we provide a practical diagnostic classification, as well as recommendations for first-line therapy and options for treating relapsed disease. Some typical clinical features of WM, such as autoimmune phenomena and 'IgM flare' after rituximab treatment, are highlighted. A more elaborate version of this guideline was published in the 'Nederlands Tijdschrift voor Hematologie' (Dutch Journal for Hematology) September 2012.

Autologous stem-cell transplantation in patients with mantle cell lymphoma beyond 65 years of age: a study from the European Group for Blood and Marrow Transplantation (EBMT).

BACKGROUND: Limited experience is available on the feasibility and efficacy of autologous stem-cell transplantation (ASCT) in patients with mantle cell lymphoma (MCL) beyond 65 years. DESIGN AND METHODS: We analysed 712 patients with MCL treated with ASCT from 2000 to 2007 and reported to the European Group for Blood and Marrow Transplantation registry. Patients>65 years were compared with patients<65 years for the end points non-relapse mortality (NRM), relapse incidence, progression-free survival (PFS), and overall survival (OS). RESULTS: Seventy-nine patients were ≥65 years old. Median time from diagnosis to ASCT was longer in the elderly patients (11 versus 9 months, P=0.005); they had more commonly received at least two treatment lines (62.0% versus 47.9%, P=0.02) and were less commonly in first complete remission at ASCT (35.4% versus 51.2%, P=0.002). Median follow-up after ASCT was 19 and 25 months, respectively. NRM was comparable at 3 months (3.8% versus 2.5%) and at 5 years (5.6% versus 5.0%). There were no differences in relapse rate (66% versus 55% at 5 years), PFS (29% versus 40%) and OS (61% versus 67%) between both populations of patients. CONCLUSION: ASCT beyond 65 years of age is feasible in selected patients with MCL and results in similar disease control and survival as in younger patients.

Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40.

Event-free survival (EFS) at 5 years in pediatric acute lymphoblastic leukemia (ALL) is >80%. Outcome in adult ALL is still unsatisfactory, which is due to less cumulative dosing of chemotherapy and less strict adherence to timing of successive cycles. In the present phase II trial, we evaluated a pediatric regimen in adult patients with ALL under the age of 40. Treatment was according to the pediatric FRALLE approach for high-risk ALL patients and characterized by increased dosages of asparaginase, steroids, methotrexate and vincristin. However, allogeneic stem cell transplantation was offered to standard risk patients with a sibling donor and to all high-risk patients in contrast to the pediatric protocol. Feasibility was defined by achieving complete remission (CR) and completion of treatment within a strict timeframe in at least 60% of patients. In all, 54 patients were included with a median age of 26. CR was achieved in 49 patients (91%), of whom 33 completed treatment as scheduled (61%). Side effects primarily consisted of infections and occurred in 40% of patients. With a median follow-up of 32 months, EFS estimated 66% at 24 months and overall survival 72%. These data show that a dose-intensive pediatric regimen is feasible in adult ALL patients up to the age of 40.

Regression of HIV-associated grade IV T cell lymphoma with combined antiretroviral therapy only.

The present report describes repeated long-term remissions of a high-grade T cell lymphoma in an HIV-positive patient upon cART only, without additional chemotherapy. A review of cases from the literature further illustrates the anti-tumor effects of cART through the induction of a strong immune reconstitution in HIV-infected patients.

Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial.

Thalidomide with melphalan/prednisone (MPT) was defined as standard treatment in elderly patients with multiple myeloma (MM) based on five randomized trials. In one of these trials, HOVON49, a prospective health-related quality-of-life (HRQoL) study was initiated in order to assess the impact of thalidomide on QoL. Patients aged >65 years with newly diagnosed MM were randomized to receive melphalan plus prednisone (MP) or MPT, followed by thalidomide maintenance in the MPT arm. Two hundred eighty-four patients were included in this side study (MP, n=149; MPT n=135). HRQoL was assessed with the EORTC Core QoL Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24) at baseline and at predetermined intervals during treatment. The QLQ-C30 subscales physical function (P=0.044) and constipation (P<0.001) showed an improvement during induction in favour of the MP arm. During thalidomide maintenance, the scores for the QLQ-MY24 paraesthesia became significantly higher in the MPT arm (P<0.001). The QLQ-C30 subscales pain (P=0.12), insomnia (P=0.068), appetite loss (P=0.074) and the QLQ-MY24 item sick (P=0.086) scored marginally better during thalidomide maintenance. The overall QoL-scale QLQ-C30-HRQoL showed a significant time trend towards more favourable mean values during protocol treatment without differences between MP and MPT. For the QLQ-C30 subscales emotional function and future perspectives, difference in favour of the MPT arm from the start of treatment was observed (P=0.018 and P=0.045, respectively) with no significant 'time × arm' interaction, indicating a persistent better patient perspective with MPT treatment. This study shows that the higher frequency of toxicity associated with MPT does not translate into a negative effect on HRQoL and that MPT holds a better patient perspective.

Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML).

Chronic myelomonocytic leukemia (CMML) characterized by cytopenias, bone marrow and peripheral blood cell dysplasia is notoriously hard to treat. Recent reclassification of CMML as a myelodysplastic/myeloproliferative (MDS/MPS) disease rather than a myelodysplastic syndrome (MDS) by the World Health Organisation (WHO) has led to a review of CMML patients treated with decitabine. Overall response rates (ORR) (complete response [CR]+partial response [PR]) in the subset of patients with CMML in one pivotal phase 3 trial (D-0007) and two phase 2 trials (PCH 95-11, PCH 97-19) decitabine were reviewed. For consistency across trials, all decitabine-treated patients were evaluated using the phase 2 response criteria (CR was defined by normocellular bone marrow with <5% blasts and normal Hgb, WBC, and platelet counts, and PR required 50% decrease in blast count, increases in Hgb by >1.5 mmol/L, WBC count by >1000, and platelet count by >50,000). A total of 31 patients diagnosed with CMML are included in this review. Similar demographics and disease characteristics were observed in all three studies, with an average age of 70.2 years and 71% of patients male. Baseline WBC of >20,000 were observed in 8/28 (29%) patients and baseline bone marrow blasts >5% in 11/28 (39%) patients. All clinical responses were centrally reviewed. The ORR was 25% (14% CR+11% PR). Hematologic improvement was observed in 11% of patients and stable disease in 39% of patients. The decitabine adverse event profile seen in CMML patients was similar to observations in other hematologic patient populations, with myelosuppression and related infectious complications. These data demonstrate encouraging activity for decitabine in CMML, and suggest that studies in other myeloproliferative diseases may be warranted.

Experience with alemtuzumab in treatment of chronic lymphocytic leukaemia in the Netherlands.

BACKGROUND: Alemtuzumab (MabCampath) is a monoclonal antibody against CD52, indicated as third-line treatment of chronic lymphocytic leukaemia (CLL). As most important side effect opportunistic infections are mentioned. It is, however, unknown whether these complications often lead to problems in general patient care in the Netherlands. METHODS: To gain insight into the use and complications of alemtuzumab therapy, the alemtuzumab-treated CLL patients in 15 hospitals in the Netherlands were evaluated by means of a questionnaire. RESULTS: In the period from 31 October 2001 until 17 November 2005, 27 patients with CLL or prolymphocytic leukaemia (PLL), RAI stage I to IV, Binet stage A to C, received 32 treatments with alemtuzumab. The time from diagnosis until start of alemtuzumab treatment was 6 +/- 4.5 years (mean +/- SD ). The treatment lasted 11 +/- 7 weeks. Of the treatments, 41% could be administered for the full 12 weeks. The most frequent adverse events were fever (72%), shivering (47%), fatigue (22%) and dyspnoea (16%). Haematological side effects consisted of leucopenia (75%), thrombocytopenia (44%), and anaemia (13%). Infectious complications occurred in 12 of 32 (38%) treatments: pneumonia (25%; of which one Pneumocystis carini pneumonia and four Aspergillus infections), sepsis (9%; of which one Listeria), herpes zoster (9%), herpes simplex (6%), CMV reactivation (6%), meningitis (3%) and Guillain Barre (3%). The overall response was 53%, with complete remission in 13%, partial remission in 41%, stable disease in 25% and progressive disease in 13%, and lasted for 8.3 +/- 7.3 months. CONCLUSION: Treatment with alemtuzumab is often terminated prematurely, leading to a suboptimal treatment effect. Fear of severe uncontrollable opportunistic infections seems unjustified.

Successful management of chronic myeloid leukaemia with leucapheresis during a twin pregnancy.

We present a 36-year-old woman in whom chronic myeloid leukaemia (CML) was diagnosed during a twin pregnancy. Because of hyperleucocytosis, we started leucapheresis also with the goal of gaining time for discussing treatment options. As this strategy was so effective and our patient was reluctant to take medication, we decided to continue this treatment.

Paraneoplastic cerebellar degeneration preceding the diagnosis of Hodgkin's lymphoma.

Paraneoplastic cerebellar degeneration (PCD) can present as a severe and (sub)acute cerebellar syndrome. PCD can accompany different kinds of neoplasms including small cell lung cancer, adenocarcinoma of the breast and ovary, and Hodgkin's lymphoma. A 34-year-old patient is described with acute dysarthria, gait ataxia and diplopia. Despite extensive laboratory and radiological evaluations in this patient with rapidly deteriorating cerebellar syndrome, the diagnosis of a paraneoplastic syndrome was only made after several months, when an anti-Tr antibody was detected in his serum. The search for Hodgkin's disease as concomitant disorder was then started and resulted in stage II B disease. The patient was successively treated with six courses of etoposide, bleomycin, vinblastine and dexamethasone and radiotherapy, which resulted in a complete remission of the Hodgkin's disease. After starting therapy the cerebellar degeneration stabilised. The pathogenesis of neuronal damage in central nervous system paraneoplastic disorders such as the one we describe is not completely understood. Antitumour therapy is assumed to be the important cornerstone in stabilising the neurological condition. Improvement of the cerebellar syndrome in anti-Tr autoantibody paraneoplastic disease is a rare achievement. Early recognition of the concomitant disorders (anti-Tr autoantibody disease and Hodgkin's lymphoma) is of crucial importance.

Quantification of outpatient management and hospitalization of patients with high-risk myelodysplastic syndrome treated with low-dose decitabine.

Intravenous low-dose 5-aza-2'-deoxycytidine (decitabine) in patients with advanced myelodysplastic syndrome (MDS) yields an approximately 50% overall response rate, including 20-25% complete remission. Decitabine-treated MDS patients can be managed as outpatients after completion of a 3-day infusion schedule. In-hospital nights (IHNs), overall survival (OS), and remaining life spent in hospital were evaluated and compared to a matched control group receiving different standard treatments. Between July 1992 and September 2001, 99 high-risk MDS patients, median age 70 years (range 49-86), were treated with low-dose decitabine. Durations of all hospitalizations were recorded. For matched-pair analysis, 44 decitabine-treated patients were matched to 44 MDS patients according to International Prognostic Scoring System classification, period of diagnosis, age, French-American-British classification, and gender. Median number of IHN across all patients was 56 and survival was 481 days, resulting in 84% of remaining life spent at home. In the matched-pair analysis, the median number of IHN was 57 in the decitabine group vs. 50 in the control group. Median survival was 400 vs. 371 days for the decitabine and control groups, respectively. Median number of remaining life spent at home was identical (83% for both groups). Matched patients who received only best supportive care (n=12) had a shorter median survival than the decitabine patients (234 vs. 400 days), and the proportion of remaining life spent at home was slightly greater (82 vs. 77%). Interestingly, matched patients with induction therapy showed comparable IHN, OS, and remaining life spent at home. In conclusion, high-risk MDS patients treated with low-dose decitabine have better survival, and spend comparable time in hospital than patients treated with supportive treatment.

An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2'-deoxycytidine (decitabine) in 177 patients.

During the last 10 years, three European phase II studies were performed to investigate the treatment of elderly patients with myelodysplastic syndrome (MDS) with low-dose 5-aza-2'-deoxycytidine (decitabine, DAC). All these European trial data were reviewed on the basis of the International Prognostic Scoring System (IPSS) risk criteria and the response criteria as recently published by an international working group. To investigate the results in a larger cohort of patients and to determine risk factors, all data were pooled with some observations from the PCH 95-06 US phase II study. The response rate in the 177 patients evaluated (median age 70 years) was 49%. The median response duration was 36 weeks, and the median survival was 15 months. Analysis of the data according to sex, age, French-American-British classification, percentage of blasts in the bone marrow, IPSS risk group, lactate dehydrogenase and cytogenetics did not reveal any factor predictive of response. Overall, 69% of patients benefited, including those with stable disease during therapy. Response duration was significantly shorter with increasing risk (according to the IPSS classification). Haemoglobin level and neutrophil count showed an inverse correlation to the IPSS classification. Univariate analysis showed a significantly inferior survival for elderly patients (>75 years of age) and for those with high levels of serum lactate dehydrogenase (LDH) (more than two times the normal values). Patients with high-risk cytogenetic abnormalities according to the IPSS risk criteria showed better overall survival than those with intermediate-risk abnormalities. When analysed according to the IPSS risk classification, high-risk patients had worse survival prospects following decitabine therapy than those with intermediate risk; however, compared to the originally reported IPPS outcomes for high-risk patients, they probably showed better survival. During the treatment period, 18% of the patients progressed towards acute leukaemia. Decitabine showed a rather low toxicity profile in this elderly patient group. In conclusion, low-dose decitabine is an active drug for the treatment of MDS patients, even for those older than 75 years with bad prognostic characteristics.

Short intensive sequential therapy followed by autologous stem cell transplantation in adult Burkitt, Burkitt-like and lymphoblastic lymphoma.

The feasibility and efficacy of up-front high-dose sequential chemotherapy followed by autologous stem cell transplantation (ASCT) in previously untreated adults (median age 33 years; range 15-64) with Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or lymphoblastic lymphoma (LyLy), both without central nervous system or extensive bone marrow involvement was investigated in a multicenter phase II study. Treatment consisted of two sequential high-dose chemotherapy induction courses incorporating prednisone, cyclophosphamide, doxorubicin, etoposide and mitoxantrone, without high-dose methotrexate or high-dose cytarabine. Patients with at least PR went on with BEAM and ASCT. Protocol treatment was completed by 23/27 (85%) BL/BLL and 13/15 (87%) LyLy patients. Median treatment duration until BEAM was 70 (range: 50-116) days. No toxic deaths occurred. Response to treatment was complete response (CR) 81% and partial response (PR) 11% for BL/BLL, CR 73% and PR 20% for LyLy. At a median follow-up of 61 months of patients still alive, six BL/BLL and eight LyLy patients have died. The actuarial 5-year overall and event-free survival estimates are 81 and 73% for BL/BLL vs 46 and 40% for LyLy patients. In conclusion, this short up-front high-dose sequential chemotherapy regimen, followed by ASCT is highly effective in adults with BL/BLL with limited bone marrow involvement, but less so in patients with LyLy.

[Modern treatment methods for multiple myeloma: guidelines from the Dutch Haemato-Oncology Association (HOVON)]. / De moderne behandeling van het multipel myeloom: een richtlijn van de Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON).

The treatment for multiple myeloma has undergone many changes over the past decade. Intensive therapy with autologous stem-cell support has improved the clinical outcome significantly in younger patients. Reduced intensity conditioning regimens have lowered the high treatment-related mortality of myeloablative allogeneic transplantation. New effective anti-myeloma drugs such as bortezomib and thalidomide analogues have become available. These new developments have made it necessary to formulate recommendations to facilitate decisions concerning the management of myeloma patients. The Myeloma Working Party of the Dutch Haemato-Oncology Association (Stichting Haemato-Oncologie voor Volwassenen Nederland) has developed therapy guidelines based on phase-II and phase-III studies as well as the expertise of the working party. These include upfront induction therapy followed by autologous transplantation for patients aged up to 65 years and oral melphalanprednisone treatment for patients with severe co-morbidities and patients over the age of 65 years. Patients under the age of 66 with an HLA-identical (family) donor are candidates for non-myeloablative stem-cell transplantation following autologous stem-cell transplantation. For second-line treatment, thalidomide, combined with dexamethasone is recommended. Younger patients responding to second-line treatment are candidates for a second autologous transplant. Bortezomib is indicated for those patients refractory to the previous two lines of treatment. All patients should receive long-term bisphosphonates. Erythropoietin may be considered in symptomatic anaemia as well as antibiotic prophylaxis during induction therapy which includes dexamethasone.

Exclusion of venous thromboembolism: evaluation of D-Dimer PLUS for the quantitative determination of D-dimer.

The objective of this study was to evaluate if D-Dimer PLUS (Dade Behring, USA), a rapid fully automated assay, could be used as an initial screening test in the diagnosis of venous thromboembolism (VTE). Samples from 274 consecutive symptomatic patients with suspected pulmonary embolism (n=229; 79% outpatients, 21% inpatients), deep venous thrombosis (n=37; 84% outpatients, 16% inpatients) or suspected for both complications (n=8) were tested with this D-dimer assay with a Sysmex CA-1500 Coagulation Analyzer. Clinical probability for pulmonary embolism (PE) or deep venous thrombosis (DVT) was staged according to a pretest risk score proposed by Wells. Final diagnosis of PE and/or DVT was established by spiral-computed tomography of the pulmonary arteries or compression ultrasonography, respectively. PE was diagnosed in 13.5% of the patients, whereas DVT was confirmed in 17.7% of the patients. The optimal cut-off value for exclusion of venous thromboembolism was 130 mug/l, and sensitivity, specificity and negative predictive value (NPV) were 95.0% (95% CI: 92.4-97.6), 30.4% (95% CI: 25.0-35.8) and 97.2% (95% CI: 95.2-99.2), respectively. In fact, two patient with PE were missed using D-Dimer PLUS; both cases were outpatients. In conclusion, this assay appears to be safe when implemented in an algorithm based on clinical assessment, D-dimer concentration, and radiological diagnostic techniques to stratify the risk for PE or DVT. However, higher sensitivities and negative predictive values were claimed in the scarce published reports for the D-Dimer PLUS assay than found in this study.